This proposal describes a 5-year training program to facilitate the transition to an independent academic position. The principal investigator has completed 4 years of post-doctoral training at the University of California, Los Angeles, and now, will expand upon his scientific skills by developing an integrative career development program consisting of both a rigorous research plan and detailed career development plan. This program will further develop several unique integrative genetics approaches to cardiovascular disease. Aldons J. Lusis will continue to mentor the principal investigator's scientific development. Dr. Lusis is a recognized leader in mouse genetics and has made several significant contributions to the understanding of atherosclerosis and lipid biology. More importantly, Dr. Lusis has successfully trained a number of investigators who have become independent academic scientist. Cardiovascular disease, CVD, remains the leading cause of death in the United States accounting for almost 1 million deaths in 2002 and an estimated economic impact in excess of 393 billion dollars in 2005. There remains limited understanding of the genes predisposing a person to death from CVD. The primary aim of this proposal is designed to use a high-resolution mapping approach recently developed in out laboratory to identify genes associated with both atherosclerotic lesion size and cellular composition. Several of these novel variants will be investigated after the trainee transitions to an independent position. In addition to gene identification, several experiments are described that characterize and test a genetic network associated with lesion size in a model of advanced atherosclerosis in the mouse. The third aim tests a novel candidate for a novel metabolite associated with atherosclerosis. The methods and analyses used in Aims 2 and 3 are the basis for gene selection and validation of novel targets identified in Aim 1 as the candidate transitions to an independent position. A long-term goal of studies proposed in this application is the identification of novel therapeutic targets for cardiovascular disease by using a systems genetics approach where mouse genetics is integrated with gene expression, small molecule metabolite profiling and extensive atherosclerotic lesion phenotyping. PUBLIC HEALTH RELEVANCE: Identifying novel genes regulating atherosclerotic plaque size and composition will discover key targets for developing new therapies for atherosclerosis, myocardial infarction and stroke.